Serotonin (5-hydroxytryptamine) which was first discovered in 1948 is one of the neurotransmitters and is one of the tryptamine derivatives, which distributed with high concentration to hypothalamic area, basal ganglion, medulla raphe nucleus and so on. Serotonin is a chemical substance contained in animals including human and is biosynthesized from tryptophan. About 10 mg of serotonin are found in human and the major part of them is distributed to chromatin cell in mucosa of small intestine. Serotonin synthesized here acts the muscle such as intestine and highly relates to the gastrointestinal tract motility. Serotonin is also found in the central nervous system and contributes mental activities in human. Much attention is being paid to the effect of serotonin from daily life to mental disorders such as depression and neurosis has been noticed. Recent years, the curative medicines against these diseases have been developed by using the medicines which effect to serotonin.
On the other hand serotonin is one of the G-protein-coupled receptors mainly in the central nervous system. Serotonin is categorized into 7 families from 5-HT1 to 5-HT7 and 14 subtypes are recognized. While the pharmacological investigations about each subtype has been continued (non-patent literature 1), three subtypes, 5-HT2A, 5-HT2B and 5-HT2c, are found in the 5-HT2 family. Furthermore, on 5-HT2B receptor various pharmacological effects have been reported to be useful for prevention or treatment of various diseases.
In general, 5-HT2B receptor antagonists are found to be useful for prevention or treatment of a variety of diseases, including migraine, inflammatory pain, nociceptive pain, fibromyalgia, chronic low back pain, visceral pain, gastroesophageal reflux disease (GERD), constipation, diarrhea, functional gastrointestinal disorder, irritable bowel syndrome (hereafter it is called IBS for short). The definition and the criteria is described in ROME III, non-patent literature 2), asthma, osteoarthritis, rheumatoid arthritis, Crohn's disease, ulcerative colitis, glomerulonephritis, nephritis, dermatitis, hepatitis, vasculitis, renal ischemia, cerebral stroke, myocardial infarction, cerebral ischemia, Alzheimer's disease, reversible airway obstruction, adult respiratory disease syndrome, chronic obstructive pulmonary disease (COPD), pulmonary hypertension (PH), idiopathic interstitial pneumonia, bronchitis, liver fibrosis, cryptogenic fibrosing alveolitis, multiple sclerosis, depression, anxiety and obesity. (non-patent literatures 3 to 7)
In addition concerning 5-HT2B receptors, the relationship of the said receptor with apparatus digestorius and pulmonary artery is known based on the experiments using 5-HT2B selective inhibitors.
Concerning the role of apparatus digestorius, 5-HT2B receptor antagonists are useful for IBS based on depressing the human intestinal contraction by electrical stimulation (patent literature 1). It is described that 5-HT2B antagonists are effective for the treatment of functional bowel disorder based on the rat intestinal contraction by serotonin stimulation (patent literature 2). In addition, reducing the pain threshold against colonic distension is reported in rats treated by 2,4,6-trinitrobenzene sulfonic acid (called TNBS hereafter), which is regarded as a visceral hypersensitivity model (non-patent literature 8).
Furthermore, 5-HT2B antagonists depressed increasing defecation weight by stress in the stress-induced defecation model in rats generally regarded as an IBS model, which can be confirmed to be useful for diarrhea-predominant IBS. In addition, when stress is given to rats, the pain response increases against colonic distension, 5-HT2B agonists suppresses the increase of the pain response.
Concerning the role at pulmonary artery, it is described that 5-HT2B receptor relates to improving the chronically hypoxic mice model of pulmonary hypertension, 5-HT2B antagonistic compounds are effective for the treatment of pulmonary hypertension (non-patent literature 9). It is reported that 5-HT2B selective antagonists showed reducing blood pressure in the early phase II study against patients with pulmonary hypertension along with chronic obstructive pulmonary disease (COPD) in the double blind test using placebo as a reference (non-patent literature 10) where 5-HT2B selective antagonists has been confirmed their safety and usefulness in human.